Atropine Eyedrops for Myopia Progression in Children and Adolescents (MODERATO STUDY)

The MODERATO study is a phase III, prospective, multicentric, randomized, double-blind, parallel group, adaptive, placebo-controlled trial. The study will be conducted in primary care and hospital settings in 3 European countries (Italy, Spain, Poland), in the UK and in Albania, involving a total of 11 centers.

The study hypothesis is that low dose (0.025% and 0.05%) of atropine eye drops will reduce the myopia progression in children and adolescents (3-18 years of age) compared with placebo eye drops, over 24 months.

A total of 234 participants from 5 countries will be estimated to take part in the study.

Eligible participants with myopia with a spherical equivalent refraction of both eyes at least -0.75 D at baseline will be randomized to treatment (0.025% atropine eye drops, 0.05% atropine eye drops) and placebo groups in 1:1:1 ratio. Each arm will consist of at least 78 individuals.

In this study, the primary objective is to evaluate efficacy of 0.025% and 0.05% atropine eye drops in children and adolescents over 24 months to slow the progression of myopia.

A formal interim efficacy analysis on the primary endpoint will be planned when the 50% of the total planned sample size has completed the 1-year treatment follow-up (105 evaluable patients in total: 35 in each arm).

"EARLY ESCAPE" Phase of Patients after Six Months of Atropine Eye Drops Treatment At the sixth month of treatment, if the patients who received the placebo treatment show worsening of their myopia, they will be switched to the active treatment. This approach is called "early escape", which ensures that the patients receive the best treatment as soon as possible, reducing the time during which they may receive ineffective treatment. The analysis will be conducted by a team of experts, Data Safety Monitoring Committee (DSMC). The treatment after the early escape will be carried out as open label study. Blinding will be maintained for the patients who do not early escape.

Analysis after One Year of Treatment When half of the patients in our study complete one year of treatment, a comprehensive analysis will be conducted to assess the effectiveness of the main treatment. This means that the results will be considered when data from 105 patients have been collected (35 in each group).

The Bayesian inference statistical technique will be used to combine and adapt the data collected during the treatment monitoring period.

Adaptive Approach

The study has been designed adaptively, which means that it can be adjusted based on the intermediate results emerging during the research. The central advantage of the adaptive design is the ability to include prospectively planned opportunities for modifying study design elements and hypotheses based upon interim data analyses. Bayesian statistics provide a method for updating information about the treatment effect as new data are observed and hence are well suited to interim analyses with accumulating efficacy data. Early stopping for statistical futility is useful in this trial as it can preserve resources that could instead be used on more promising active arms and prevent patients from being given an ineffective experimental treatment dosage. After one year of treatment, for half of the participants there are several scenarios that may occur:

• If there are 8 or fewer people who respond positively in each group of patients who have received the active treatment (the treatment with medication), there should be the discontinuation of that treatment group as it is deemed ineffective.
• If there are 27 or more patients who respond positively in both active treatment groups, there should be the discontinuation of the placebo treatment group, as it is confirmed that the active treatment is working well.
• If there is a significant difference in treatment response between the active groups but the necessary number of patients to discontinue the placebo treatment arm is not reached, it could be hypothesized that the active treatment is advantageous, and the sample size of patients should be reassessed to confirm this hypothesis.

After the End of Study visit, no Follow-Up visits are foreseen. The following assessments will be performed throughout the conduction of study: Refraction test for measuring visual acuity (VA) (near and distance); Pupil diameter (PD) in photopic lighting conditions; Accommodation amplitude; Intraocular Pressure Measurement; Stereopsis; Slit lamp examination; Macular/optic disc examination by age appropriate methods (e.g. fundoscopy, or fundus photo); Ocular biometry; Instillation of cycloplegic agents, different participating site will follow their standard cycloplegic regimen (1% Tropicamide and 1% cyclopentolate eye drop); Cycloplegic autorefraction (to evaluate the refractive power of the eye); Measurement of prescription in current glasses (focimetry); Urine pregnancy test; Adverse event (AE)/Serious Adverse Event (SAE) assessments; Questionnaires (Student Refractive Error and Eyeglasses Questionnaire - Revised (SREEQ-R), Visual Light Sensitivity Questionnaire-8 (VLSQ-8), 3-items questionnaire for acceptability of the formulation) will be used.

Inclusion criteria

• Males and females, aged from 3 to less than 18 years.
• Subjects showing myopia with a spherical equivalent refraction of both eyes at least -0.75 D at baseline.
• The intraocular pressure in each eye must be equal or less than 21 mmHg.
• The parents or the legal representative must be informed about the clinical trial and must sign the informed consent form. The exception to consider is related to the individuals aged above 16 years only in the UK, who can provide their own consent according to the local regulations.
• Women with childbearing potential (WOCBP) (after menarche) who have a negative highly sensitive urine dipstick pregnancy test. Additional pregnancy testing during the study will be conducted at visits 1, 2, 3, 4, 5, 6.
• WOCBP or males who are using a highly effective birth control method to prevent pregnancies. Eligible highly effective contraceptive methods for WOCBP are combined (which contain estrogen and progestogen) hormonal contraception associated with inhibition of ovulation (oral, intravaginal (inside of the vagina), transdermal (through the skin)); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (small devices that are placed inside uterus to prevent pregnancies); intrauterine hormone-releasing system. Sexual abstinence represents a highly effective contraceptive method, if in line with the subject's normal habits.

Exclusion criteria

• Anisometropia, meaning a significant difference in refractive power between the two eyes exceeding |1.5| D.
• Refractive astigmatism exceeding |1.5| D.
• Presence of ocular pathologies such as pathological myopia, corneal scars, or other anterior or posterior eye pathologies.
• History of amblyopia or strabismus.
• Presence of a history of a retinal dystrophy or systemic disorder that may predispose to severe myopia (e.g., Marfan syndrome, retinitis pigmentosa, Stickler syndrome, retinopathy of prematurity)
• Abnormalities in ocular biometry, except for axial length or previous intraocular or ocular laser/non-laser surgery.
• History of glaucoma or narrow angles in the anterior chamber of the eye.
• Conditions such as Down syndrome or spastic paralysis.
• Known intolerance or allergies to atropine eye drops or hypersensitivity to any component of the atropine eye drops.
• Pregnancy or breastfeeding.
• History of alcohol or drug abuse.
• Mental or emotional instability that could interfere with study procedures.
• Lack of reliability or cooperation from the patient.
• Any treatment received for myopia within the past three months prior to inclusion in the study.
• Other reasons, at the discretion of the investigator that may deem the subject's participation in the study inappropriate.
• Patients who have consented to participate in the clinical trial, but do not meet one or more eligibility criteria required for participation in the trial during the screening procedures, and subsequently are not randomly assigned to the study treatment or entered in the study, are considered screening failures.